The abuse of amphetamine and its congeners remains a significant public health problem. We have previously demonstrated dramatic neurochemical alterations after toxic doses of methamphetamine (METH). Profound decreases in tryptophan and tyrosine hydroxylase activities, as well as depression of concentrations of 5-hydroxytryptamine (5HT) and dopamine (DA), in selected brain regions have been observed; concurrent changes in brain neuropeptide concentrations have also been found. We have accumulated evidence that dopamine may be involved in the neurochemical alterations observed. Our objectives in this proposal are to elucidate the role of endogenous DA in causing the alterations in brain serotonergic and peptidergic systems which result from the administration of large doses of METH. Endogenous dopamine release will be decreased with 6-hydroxydopamine or increased by sensitization of the rat with prior repeated daily doses of METH. The site(s) of the METH-induced response will be investigated by local injections into specific brain areas of dopamine antagonists; systemic administration of these agents prevents the METH- induced alteration of serotonergic and peptidergic systems. The roles of several peptidergic as well as cholinergic nervous systems in the METH-induced response will also be determined. The analytical procedures used in the study are currently operational in our laboratory. The studies outlined in this proposal are pertinent in understanding the complex mechanism(s) responsible for the marked changes occurring in brain biogenic amine and neuropeptide systems when toxic doses of METH are administered. Moreover, the observations made in these studies should provide valuable information in establishing the interrelationships between the serotonergic, dopaminergic, cholinergic and peptidergic systems in the brain.